Presentations, management and outcomes of postoperative bariatric patients seen in the emergency department.

BACKGROUND: Bariatric surgery is becoming increasingly common and postoperative patients often present to the emergency department (ED) with complications. We sought to describe the presenting complaints, management, and outcomes of postoperative bariatric surgery patients seen in the ED. METHODS: We conducted a health records review of 300 consecutive postoperative Roux-en-Y bypass surgery patients who presented to two tertiary care EDs of a major bariatric surgery center within one year of surgery. Cases were identified using a data analytic tool, and two evaluators abstracted clinical variables, imaging, treatments, and outcomes using the electronic health record. Attending emergency physicians verified the data and an experienced bariatric surgeon interpreted the computed tomography (CT) results and surgical procedures. RESULTS: We included 300 patients with mean age 43.0 years, 89.7% female. Of these, 70.0% presented within 30 days of surgery and 41.7% were admitted to hospital. ED treatments included intravenous fluids (67.0%), antiemetics (53.3%), and analgesia (61.9%). Patients presenting within 30 days of surgery were more likely to undergo a CT (74.3% vs 63.3%; p = 0.06) and to have clinically important CT findings (31.9% vs 6.6%; p ≤0.001). More of the ≤30-day patients were admitted to hospital (46.2% vs 31.1%; p = 0.02). While a higher proportion of patients presenting after 30 days underwent a procedure, a large number of those were not directly related to bariatric surgery, such as appendectomy and cholecystectomy. Of the 34 patients undergoing a procedure, the majority presented with abdominal pain (76.5%). CONCLUSION: This is the first detailed health records review of postoperative bariatric patients seen in the ED in the emergency medicine literature. Those presenting with abdominal pain were more likely to undergo CT abdomen and a surgical procedure. Similarly, those presenting within 30 days of surgery were more likely to have significant CT findings and require hospital admission. Others presenting with primarily nausea and vomiting may improve with ED symptom management and be discharged home with bariatric team follow-up.

Convergent evolution of BRCA2 reversion mutations under therapeutic pressure by PARP inhibition and platinum chemotherapy.

Reversion mutations that restore wild-type function of the BRCA gene have been described as a key mechanism of resistance to Poly(ADP-ribose) polymerase (PARP) inhibitor therapy in BRCA-associated cancers. Here, we report a case of a patient with metastatic castration-resistant prostate cancer (mCRPC) with a germline BRCA2 mutation who developed acquired resistance to PARP inhibition. Extensive genomic interrogation of cell-free DNA (cfDNA) and tissue at baseline, post-progression, and postmortem revealed ten unique BRCA2 reversion mutations across ten sites. While several of the reversion mutations were private to a specific site, nine out of ten tumors contained at least one mutation, suggesting a powerful clonal selection for reversion mutations in the presence of therapeutic pressure by PARP inhibition. Variable cfDNA shed was seen across tumor sites, emphasizing a potential shortcoming of cfDNA monitoring for PARPi resistance. This report provides a genomic portrait of the temporal and spatial heterogeneity of prostate cancer under the selective pressure of a PARP inhibition and exposes limitations in the current strategies for detection of reversion mutations.

Immunostimulant effects of Pituitary Adenylate Cyclase-Activating Polypeptide and double-stranded (ds)RNA in Orconectes propinquus.

Disease outbreaks in crustacean aquaculture caused by opportunistic and obligate pathogens cause severe economic losses to the industry. Antibiotics are frequently used as prophylactic treatments worldwide, although its overuse and misuse has led to microbial resistance, which has driven the search for novel molecules with immunostimulant and antibacterial activities. Antimicrobial peptides (AMP) and double-stranded (ds)RNAs constitute promising immunostimulants in the fight against infectious diseases in aquaculture. Scientists have made significant progress in testing these molecules in aquatic organisms as potential candidates for replacing conventional antibiotics. However, most studies have been conducted in teleost fish, thus little is known about the immunostimulatory effects in crustaceans, especially in freshwater crayfishes. Consequently, in the present work, we evaluate the immunomodulatory effects of the AMP Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and high molecular weight (HMW) Poly (I:C) in the northern clearwater crayfish Orconectes propinquus. Two bioassays were conducted to evaluate the effects of different doses of PACAP and Poly (I:C) HMW, different administration routes, as well as the effects of the combined treatment on the crayfish immune system. Results showed the immunostimulatory role of PACAP and Poly (I:C) HMW with effects depending on the dose, the site of injection and the treatment assessed. These findings offer new insights into the crayfish immune system and contribute to the development of effective broad-spectrum immune therapies in aquaculture.

Outcomes of acute heart failure patients managed in the emergency department.

BACKGROUND: Acute heart failure is a serious condition commonly seen in the emergency department (ED). The HEARTRISK6 Scale has been recently developed to identify the risk of poor outcomes but has not been tested. We sought to describe the management and outcomes of ED patients with acute heart failure and to evaluate the potential impact of the HEARTRISK6 Scale. METHODS: We conducted a health records review of 300 consecutive acute heart failure patients presenting to two tertiary care EDs. Two evaluators abstracted clinical variables, ED management and treatment details, and patient outcomes using the electronic health records platform (EPIC) and attending physicians verified the data. The primary outcome measure was a short-term serious outcome, as shown in Results. In addition, the HEARTRISK6 score was calculated retrospectively. RESULTS: We included 300 patients with mean age of 78.5 years, 51.0% male, 56.3% arrival by ambulance, and 67.0% admitted to hospital. 25.3% experienced a short-term serious outcome 1) after admission (N = 201): non-invasive ventilation 14.9%, intubation 1.5%, major cardiac procedure 5.0%, myocardial infarction 2.0%, death 8.5%; 2) after ED discharge (N = 99): return to ED 21.2%, death 4.0%. Those initially admitted experienced a much higher proportion of serious outcomes compared to those discharged (29.9% vs. 16.2%). A HEARTRISK6 Scale cut-point score of ≥ 1 would have had a sensitivity of 91.0%, specificity 24.5%, and negative likelihood ratio 0.37 for short-term serious outcomes and suggested hospital admission for 80.7% of cases. CONCLUSION: There was a large range of severity of illness of acute heart failure patients and a wide variety of treatments were administered in the ED. Both admitted and discharged patients experienced a high proportion of poor outcomes. The HEARTRISK6 Scale showed a high sensitivity for short-term serious outcomes but with the potential to increase hospital admissions. Further validation of the HEARTRISK6 Scale is required before routine clinical use.

RéSUMé: ARRIèRE-PLAN: L'insuffisance cardiaque aiguë est une affection grave couramment observée à l'urgence. L'échelle HEARTRISK6 a été mise au point récemment pour identifier le risque de mauvais résultats, mais n'a pas été testée. Nous avons cherché à décrire la prise en charge et les résultats des patients atteints d'insuffisance cardiaque aiguë et à évaluer l'impact potentiel de l'échelle HEARTRISK6. MéTHODES: Nous avons effectué un examen des dossiers de santé de 300 patients atteints d'insuffisance cardiaque aiguë consécutifs qui se présentaient à deux SU de soins tertiaires. Deux évaluateurs ont résumé les variables cliniques, les détails de la gestion et du traitement des SU et les résultats pour les patients à l'aide de la plateforme de dossiers de santé électroniques (EPIC). et les médecins traitants ont vérifié les données. La principale mesure des résultats était le résultat grave à court terme, comme le montrent les résultats. De plus, le score HEARTRISK6 a été calculé rétrospectivement. RéSULTATS: Nous avons inclus 300 patients âgés en moyenne de 78,5 ans, 51,0 % d'hommes, 56,3 % d'arrivées par ambulance et 67,0 % d'hospitalisations. 25,3 % ont connu un résultat grave à court terme 1) après l'admission (N=201) : ventilation non invasive 14,9 %, intubation 1,5 %, procédure cardiaque majeure 5,0 %, infarctus du myocarde 2,0 %, décès 8,5 %; 2) après le congé de l'urgence (N=99) : retour à l'urgence 21,2 %, décès 4,0 %. Les personnes admises au départ ont connu une proportion beaucoup plus élevée de résultats graves que les personnes libérées (29,9 % contre 16,2 %). Une note de seuil de 1 sur l'échelle HEARTRISK6 aurait eu une sensibilité de 91,0 %, une spécificité de 24,5 % et un ratio de probabilité négatif de 0,37 pour les résultats graves à court terme et une admission à l'hôpital suggérée pour 80,7 % des cas. CONCLUSION: Il y avait un large éventail de gravité de la maladie des patients atteints d'insuffisance cardiaque aiguë et une grande variété de traitements ont été administrés à l'urgence. Les patients admis et libérés ont connu une forte proportion de mauvais résultats. L'échelle HEARTRISK6 a montré une sensibilité élevée pour les résultats graves à court terme, mais avec le potentiel d'augmenter les admissions à l'hôpital. Une validation plus poussée de l'échelle HEARTRISK6 est nécessaire avant l'utilisation clinique de routine.

An Initial Evaluation of Human Plasma cMLC-1: A Potential Protein Biomarker for Trastuzumab-Induced Cardiotoxicity, Breast Cancer Screening and Progression.

Background: Trastuzumab is a targeted therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, trastuzumab-induced cardiotoxicity (TIC) has been reported when trastuzumab is administered to patients as a single agent or combined with anthracycline. Currently no means for detecting the early onset of TIC such as a protein biomarker is available. In this regard and based on promising results from a preliminary animal study, the potential of cardiac myosin light chain 1(cMLC-1) as a biomarker to predict TIC, screen patients for breast cancer and monitor tumor progression in breast cancer patients was evaluated. Methods: Archived plasma samples collected before and after trastuzumab treatment at various fixed time points from 15 HER2+ patients with or without cardiotoxicity, recently collected plasma samples from 79 breast cancer patients (40 HER2+, 39 HER2-), and 46 healthy donors were analyzed for cMLC-1 levels using an enzyme-linked immunosorbent assay (ELISA). Results: An elevated plasma cMLC-1 level was found to be associated with TIC in 3 out of 7 (43%) trastuzumab-treated HER2+ breast cancer patients. However, this study provided an opportunity for us to study plasma cMCL-1 levels in breast cancer patients. It was demonstrated that elevated plasma cMCL-1 is associated with breast cancer. The cutoff cMLC-1 concentration is estimated to be 44.99 ng/mL with a sensitivity of 59.49% (95%CI: 48.47%-69.63%) and specificity of 71.74% (95%CI: 57.45% -82.68%). We also found a noticeable but not significantly more elevated plasma cMCL-1 level in HER2- than in HER2+ breast cancer patients with the given sample sizes. As a result, improved sensitivity of 79.49% (95%CI: 64.47%-89.22%) with the specificity of 63.04% (95%CI:48.60%-75.48%) were obtained for cMLC-1 to predict HER2- breast cancer with the cutoff at 37.17 ng/mL. Moreover, this study determined that cMLC-1 level was significantly higher in patients with metastatic breast cancer than in patients with non-metastatic breast cancer. Conclusions: While the analysis of cMLC-1 levels in the plasma of a limited number of trastuzumab-treated HER2+ breast cancer patients failed to fully support its identification as a blood protein biomarker for predicting TIC, additional analyses of plasma cMLC-1 levels did significantly establish its correlations with breast cancer and disease progression. Our findings shed light on and filled, to some extent, the gap of knowledge of the potential of cMLC-1 as a blood protein biomarker for screening breast cancer and monitoring disease progression of breast cancer.

EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma.

FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma. SIGNIFICANCE: We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.

Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG), the first antibody-drug conjugate (ADC) approved for triple-negative breast cancer, incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and postprogression specimens. One patient exhibiting de novo progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical TOP1 E418K resistance mutation and subsequent frameshift TOP1 mutation, whereas a distinct branch exhibited a novel TACSTD2/TROP2 T256R missense mutation. Reconstitution experiments demonstrated that TROP2T256R confers SG resistance via defective plasma membrane localization and reduced cell-surface binding by hRS7. These findings highlight parallel genomic alterations in both antibody and payload targets associated with resistance to SG. SIGNIFICANCE: These findings underscore TROP2 as a response determinant and reveal acquired SG resistance mechanisms involving the direct antibody and drug payload targets in distinct metastatic subclones of an individual patient. This study highlights the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance.This article is highlighted in the In This Issue feature, p. 2355.

Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.

PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer.

The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers.

Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood-brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis. SIGNIFICANCE: Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo-cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.This article is highlighted in the In This Issue feature, p. 1.

Multiomics Profiling Establishes the Polypharmacology of FDA-Approved CDK4/6 Inhibitors and the Potential for Differential Clinical Activity.

The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five different phenotypic and biochemical assays to compare approved inhibitors of cyclin-dependent kinases 4/6-collectively regarded as breakthroughs in the treatment of hormone receptor-positive breast cancer. We find that transcriptional, proteomic, and phenotypic changes induced by palbociclib, ribociclib, and abemaciclib differ significantly; abemaciclib in particular has advantageous activities partially overlapping those of alvocidib, an older polyselective CDK inhibitor. In cells and mice, abemaciclib inhibits kinases other than CDK4/6 including CDK2/cyclin A/E-implicated in resistance to CDK4/6 inhibition-and CDK1/cyclin B. The multifaceted experimental and computational approaches described here therefore uncover underappreciated differences in CDK4/6 inhibitor activities with potential importance in treating human patients.

The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression.

Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF-NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF-NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF-NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ-TEAD transcriptional target. We also discovered that VEGF-NRP2-YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF-NRP2 or YAP/TAZ. These findings reveal roles for VEGF-NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF-NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.

Color inference in visual communication: the meaning of colors in recycling.

People interpret abstract meanings from colors, which makes color a useful perceptual feature for visual communication. This process is complicated, however, because there is seldom a one-to-one correspondence between colors and meanings. One color can be associated with many different concepts (one-to-many mapping) and many colors can be associated with the same concept (many-to-one mapping). We propose that to interpret color-coding systems, people perform assignment inference to determine how colors map onto concepts. We studied assignment inference in the domain of recycling. Participants saw images of colored but unlabeled bins and were asked to indicate which bins they would use to discard different kinds of recyclables and trash. In Experiment 1, we tested two hypotheses for how people perform assignment inference. The local assignment hypothesis predicts that people simply match objects with their most strongly associated color. The global assignment hypothesis predicts that people also account for the association strengths between all other objects and colors within the scope of the color-coding system. Participants discarded objects in bins that optimized the color-object associations of the entire set, which is consistent with the global assignment hypothesis. This sometimes resulted in discarding objects in bins whose colors were weakly associated with the object, even when there was a stronger associated option available. In Experiment 2, we tested different methods for encoding color-coding systems and found that people were better at assignment inference when color sets simultaneously maximized the association strength between assigned color-object parings while minimizing associations between unassigned pairings. Our study provides an approach for designing intuitive color-coding systems that facilitate communication through visual media such as graphs, maps, signs, and artifacts.